tbuckley/cabot-search huggingface dataset:
Expression and functions of transient receptor potential channels in liver diseases
Authors: Wenhui Wang, Pengyu Liu, Yalin Zhang, Li Yan, Michael X. Zhu, Jin Wang, Ye Yu
Journal: Acta Pharmaceutica Sinica B (2022)

Liver diseases constitute a major healthcare burden globally, including acute hepatic injury resulted from acetaminophen overdose, ischemia-reperfusion or hepatotropic viral infection and chronic hepatitis, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC). Attainable treatment strategies for most liver diseases remain inadequate, highlighting the importance of substantial pathogenesis. The transient receptor potential (TRP) channels represent a versatile signalling mechanism regulating fundamental physiological processes in the liver. It is not surprising that liver diseases become a newly explored field to enrich our knowledge of TRP channels. Here, we discuss recent findings revealing TRP functions across the fundamental pathological course from early hepatocellular injury caused by various insults, to inflammation, subsequent fibrosis and hepatoma. We also explore expression levels of TRPs in liver tissues of ALD, NAFLD and HCC patients from Gene Expression Omnibus (GEO) or The Cancer Genome Atlas (TCGA) database and survival analysis estimated by Kaplan-Meier Plotter. At last, we address the therapeutical potential and challenges by pharmacologically targeting TRPs to treat liver diseases. The aim is to provide a better understanding of the implications of TRP channels in liver diseases, contributing to the discovery of novel therapeutic targets and efficient drugs.
2021 EULAR points to consider to support people with rheumatic and musculoskeletal diseases to participate in healthy and sustainable paid work
Authors: Annelies Boonen, Casper Webers, Maarten Butink, Birgit Barten, Neil Betteridge, Dame Carol Black, Ann Bremander, Boryana Boteva, Olga Brzezińska, Lina Chauhan, Sarah Copsey, Vera Guimarães, Monique Gignac, Jennifer Glaysher, Frans Green, Jan L Hoving, Mary Lucy Marques, Hana Smucrova, Tanja A Stamm, Dieter Wiek, Ross Wilkie, Anthony D Woolf, Gerd R Burmester, Johannes W Bijlsma, Suzanne M M Verstappen
Journal: Annals of the Rheumatic Diseases (2022)

Aim As part of its strategic objectives for 2023, EULAR aims to improve the work participation of people with rheumatic and musculoskeletal diseases (RMDs). One strategic initiative focused on the development of overarching points to consider (PtC) to support people with RMDs in healthy and sustainable paid work participation. Methods EULAR’s standardised operating procedures were followed. A steering group identified six research areas on paid work participation. Three systematic literature reviews, several non-systematic reviews and two surveys were conducted. A multidisciplinary taskforce of 25 experts from 10 European countries and Canada formulated overarching principles and PtC after discussion of the results of literature reviews and surveys. Consensus was obtained through voting, with levels of agreement obtained anonymously. Results Three overarching principles and 11 PtC were formulated. The PtC recognise various stakeholders are important to improving work participation. Five PtC emphasise shared responsibilities (eg, obligation to provide active support) (PtC 1, 2, 3, 5, 6). One encourages people with RMDs to discuss work limitations when necessary at each phase of their working life (PtC 4) and two focus on the role of interventions by healthcare providers or employers (PtC 7, 8). Employers are encouraged to create inclusive and flexible workplaces (PtC 10) and policymakers to make necessary changes in social and labour policies (PtC 9, 11). A research agenda highlights the necessity for stronger evidence aimed at personalising work-related support to the diverse needs of people with RMDs. Conclusion Implementation of these EULAR PtC will improve healthy and sustainable work participation of people with RMDs.
Reduced lung function and health-related quality of life after treatment for pulmonary tuberculosis in Gambian children: a cross-sectional comparative study
Authors: Esin Nkereuwem, Schadrac Agbla, Azeezat Sallahdeen, Olumuyiwa Owolabi, Abdou K Sillah, Monica Genekah, Abdoulie Tunkara, Sheriff Kandeh, Maryama Jawara, Lamin Saidy, Andrew Bush, Toyin Togun, Beate Kampmann
Journal: Thorax (2022)

Background Post-tuberculosis (post-TB) lung disease is an under-recognised consequence of pulmonary tuberculosis (pTB). We aimed to estimate the prevalence of residual lung function impairment and reduced health-related quality of life (HRQoL) in children after pTB treatment completion. Methods We conducted a cross-sectional comparative study of children aged less than 15 years at TB diagnosis who had completed treatment for pTB at least 6 months previously with a comparator group of age-matched children without a history of pTB. Symptoms, spirometry and HRQoL measured with PedsQL scale were collected. Variables associated with lung function impairment were identified through logistic regression models. Results We enrolled 68 post-TB cases (median age 8.9 (IQR 7.2–11.2) years) and 91 children in the comparison group (11.5 (8.0–13.7) years). Spirometry from 52 (76.5%) post-TB cases and 89 (94.5%) of the comparison group met the quality criteria for acceptability and repeatability. Lung function impairment was present in 20/52 (38.5%) post-TB cases and 15/86 (17.4%) in the comparison group, p=0.009. Previous pTB and a history of chronic cough were significantly associated with the presence of lung function impairment (p=0.047 and 0.006 respectively). Forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC) and FEV 1 /FVC z -scores were significantly lower in the post-TB cases compared with the comparison group (p= &lt;0.001, 0.014 and &lt;0.001, respectively). The distribution of the self-reported physical health score, and parent-reported physical, emotional, psychological, social and total HRQoL scores were significantly lower in the post-TB cases compared with the comparison group. Conclusions Previous TB in children is associated with significantly impaired lung function and HRQoL.
Variability of strain engraftment and predictability of microbiome composition after fecal microbiota transplantation across different diseases
Authors: Gianluca Ianiro, Michal Punčochář, Nicolai Karcher, Serena Porcari, Federica Armanini, Francesco Asnicar, Francesco Beghini, Aitor Blanco-Míguez, Fabio Cumbo, Paolo Manghi, Federica Pinto, Luca Masucci, Gianluca Quaranta, Silvia De Giorgi, Giusi Desirè Sciumè, Stefano Bibbò, Federica Del Chierico, Lorenza Putignani, Maurizio Sanguinetti, Antonio Gasbarrini, Mireia Valles-Colomer, Giovanni Cammarota, Nicola Segata
Journal: Nature Medicine (2022)

Fecal microbiota transplantation (FMT) is highly effective against recurrent Clostridioides difficile infection and is considered a promising treatment for other microbiome-related disorders, but a comprehensive understanding of microbial engraftment dynamics is lacking, which prevents informed applications of this therapeutic approach. Here, we performed an integrated shotgun metagenomic systematic meta-analysis of new and publicly available stool microbiomes collected from 226 triads of donors, pre-FMT recipients and post-FMT recipients across eight different disease types. By leveraging improved metagenomic strain-profiling to infer strain sharing, we found that recipients with higher donor strain engraftment were more likely to experience clinical success after FMT (P = 0.017) when evaluated across studies. Considering all cohorts, increased engraftment was noted in individuals receiving FMT from multiple routes (for example, both via capsules and colonoscopy during the same treatment) as well as in antibiotic-treated recipients with infectious diseases compared with antibiotic-naïve patients with noncommunicable diseases. Bacteroidetes and Actinobacteria species (including Bifidobacteria) displayed higher engraftment than Firmicutes except for six under-characterized Firmicutes species. Cross-dataset machine learning predicted the presence or absence of species in the post-FMT recipient at 0.77 average AUROC in leave-one-dataset-out evaluation, and highlighted the relevance of microbial abundance, prevalence and taxonomy to infer post-FMT species presence. By exploring the dynamics of microbiome engraftment after FMT and their association with clinical variables, our study uncovered species-specific engraftment patterns and presented machine learning models able to predict donors that might optimize post-FMT specific microbiome characteristics for disease-targeted FMT protocols.
Abstract IA004: Mesenchymal progenitors and sarcomagenesis
Authors: T. Michael Underhill
Journal: Clinical Cancer Research (2022)

Abstract Synovial sarcoma (SS) is an aggressive soft-tissue malignancy that can arise in any area of the body, and most frequently affects adolescents and young adults. The 10-year survival rate has been estimated at 50%. SS is characterized by a pathognomonic t(X;18)(p11.2;q11.2) translocation which produces a fusion oncogene named SS18-SSX. In mouse models, expression of SS18-SSX is sufficient to drive the development of SS-like tumors. Despite recent advancements in our understanding of SS biology, the cell of origin remains undefined. In most instances, it is likely mesenchymal in nature. We previously generated a mesenchymal progenitor (MP) specific Cre line that has enabled us to identify MPs within the embryo [MOU1], and characterize and define their lineage trajectories through development into the adult. This line has been used to generate a unique mouse model of SS where the human SS18-SSX fusion oncogene with an EGFP marker is conditionally expressed in adult MPs. This model shows 100% penetrant SS tumor formation with a median latency period of 16 weeks. Histologic analyses of tumors reveal characteristic cellular morphology and the expression of common markers of SS. Single-cell (sc) RNA-seq gene expression profiles of murine tumors recapitulate those observed in human SS samples and highlight genetic programs involved in sarcomagenesis. Using this model, we can identify and isolate neoplastic lesions prior to the development of grossly visible tumors and trace these cells through the complete transformation continuum. By comparing tumor cells to normal MPs, we aim to better understand the mechanisms underlying the SS18-SSX induced transformation of MPs. Together, this model identifies a cell of origin for SS and provides us with a unique opportunity to address the molecular and cellular drivers of SS. Citation Format: T. Michael Underhill. Mesenchymal progenitors and sarcomagenesis [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr IA004.
Abstract B017: Tumor-secreted collagen VI weakens endothelium and promotes metastasis
Authors: Ying Liu, Ashley M. Fuller, Ileana Murazzi, Ann Devine, Nicolas Skuli
Journal: Clinical Cancer Research (2022)

Abstract Metastasis is the leading cause of cancer-related deaths. However, the mechanisms behind the metastatic cascade remain poorly understood. Tumor’s metastatic potential is strongly influenced by microenvironmental cues such as low oxygen (hypoxia). Our published work reported that lung metastases in sarcoma are associated with increased primary tumor expression of the hypoxia-inducible collagen-modifying lysyl hydroxylase, Plod2; in multiple subtypes of sarcoma, excessive collagen lysyl hydroxylation results in secretion of immature collagen aggregates able to physically associate with tumor cells and promote both intravasation and extravasation. In the current study, we observed that Plod2 is colocalized with collagen VI and is important for its extracellular network structure, suggesting that collagen VI is a putative substrate of Plod2. Using an impedance sensing assay and a zebrafish intravital microinjection model, we demonstrated that tumoral Plod2 and collagen VI weaken the endothelial barrier and promote extravasation. With a tail vein injection mouse model, we determined that collagen VI is essential for lung metastasis. Clinically, we detected high levels of collagen VI in metastatic sarcoma in surgically resected patient lungs. Furthermore, by analyzing patient data in The Cancer Genome Atlas (TCGA), we found a strong correlation between the expression of both PLOD2 and collagen VI with disease outcomes. Together, our study identifies a novel mechanism of sarcoma lung metastasis, opening up opportunities for therapeutic intervention. Citation Format: Ying Liu, Ashley M. Fuller, Ileana Murazzi, Ann Devine, Nicolas Skuli. Tumor-secreted collagen VI weakens endothelium and promotes metastasis [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr B017.
A systematic review of digital and face-to-face cognitive behavioral therapy for depression
Authors: Lana Kambeitz-Ilankovic, Uma Rzayeva, Laura Völkel, Julian Wenzel, Johanna Weiske, Frank Jessen, Ulrich Reininghaus, Peter J. Uhlhaas, Mario Alvarez-Jimenez, Joseph Kambeitz
Journal: npj Digital Medicine (2022)

Abstract Cognitive behavioral therapy (CBT) represents one of the major treatment options for depressive disorders besides pharmacological interventions. While newly developed digital CBT approaches hold important advantages due to higher accessibility, their relative effectiveness compared to traditional CBT remains unclear. We conducted a systematic literature search to identify all studies that conducted a CBT-based intervention (face-to-face or digital) in patients with major depression. Random-effects meta-analytic models of the standardized mean change using raw score standardization (SMCR) were computed. In 106 studies including n = 11854 patients face-to-face CBT shows superior clinical effectiveness compared to digital CBT when investigating depressive symptoms ( p &lt; 0.001, face-to-face CBT: SMCR = 1.97, 95%-CI: 1.74–2.13, digital CBT: SMCR = 1.20, 95%-CI: 1.08–1.32) and adherence ( p = 0.014, face-to-face CBT: 82.4%, digital CBT: 72.9%). However, after accounting for differences between face-to-face and digital CBT studies, both approaches indicate similar effectiveness. Important variables with significant moderation effects include duration of the intervention, baseline severity, adherence and the level of human guidance in digital CBT interventions. After accounting for potential confounders our analysis indicates comparable effectiveness of face-to-face and digital CBT approaches. These findings underline the importance of moderators of clinical effects and provide a basis for the future personalization of CBT treatment in depression.
Abstract A017: Multiple intratumoral sources of kit ligand promote oncogenic kit signaling in gastrointestinal stomal tumor
Authors: Andrew D. Tieniber, Ferdinando Rossi, Andrew Hanna, Mengyuan Liu, Mark Etherington, Kevin Do, Laura Wang, Ronald P. DeMatteo
Journal: Clinical Cancer Research (2022)

Abstract Introduction: Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and is typically driven by a single mutation in the Kit receptor. While highly effective, tyrosine kinase inhibitors like imatinib are not curative. The natural ligand for the Kit receptor is Kit Ligand (KitL), which exists in both soluble and membrane-bound forms. We sought to determine the role of KitL in the oncogenic Kit signaling of GIST. Methods: KitV558Δ/+ mice, which spontaneously develop an intestinal GIST, were treated with imatinib or vehicle for 1 week, and sorted non-immune (CD45-) cells from tumors were submitted for single-cell RNA sequencing (n=3/group). GIST T1 cells were treated with KitL with or without imatinib and oncogenic Kit signaling was evaluated. KitV558Δ/+ mice were crossed with various KitL mutant and inducible models and tumor weights were measured (n=3-4/group). Human GISTs were stained for KitL expression by IHC, and an existing bulk RNA sequencing human GIST dataset with matched human serum was analyzed. Results: Unsupervised clustering revealed endothelial, smooth muscle, and tumor cells had high expression of KitL RNA in untreated tumors from KitV558Δ/+ mice. Imatinib therapy increased KitL RNA in all 3 cell types, suggesting that extra-tumoral KitL expression is dependent on oncogenic signaling (p&amp;lt;0.05). In GIST T1 cells, exogenous KitL increased Kit activation and reduced imatinib’s efficacy. Tumors from mice with homozygous KitL deletion (KitV558Δ/+;Etv1Cre-ERT2/+;KitLflox/flox) were smaller than tumors from littermates with heterozygous KitL deletion (KitV558Δ /+;Etv1Cre-ERT2/+;KitLflox/+), providing evidence that KitL contributes to GIST development in vivo despite the presence of mutated Kit (p&amp;lt;0.05). Furthermore, tumors from KitV558Δ/+;KitLKitL1Δ/KitL1Δ mice, which lack the proteolytic cleavage site for soluble KitL, were smaller than matched KitV558Δ/+ mice, indicating that soluble KitL is important for maximal tumor growth in vivo (p&amp;lt;0.05). Heterogeneous KitL expression was confirmed in human GISTs by IHC. Human serum contained more KitL in patients with tumors resistant to imatinib and in those with tumors expressing more KitL RNA(p&amp;lt;0.05). Conclusions: KitL is produced by multiple cell types within GIST and contributes to oncogenesis. Targeting KitL may be important for optimal tumor therapy. Citation Format: Andrew D. Tieniber, Ferdinando Rossi, Andrew Hanna, Mengyuan Liu, Mark Etherington, Kevin Do, Laura Wang, Ronald P. DeMatteo. Multiple intratumoral sources of kit ligand promote oncogenic kit signaling in gastrointestinal stomal tumor [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A017.
Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus
Authors: Andreas Mackensen, Fabian Müller, Dimitrios Mougiakakos, Sebastian Böltz, Artur Wilhelm, Michael Aigner, Simon Völkl, David Simon, Arnd Kleyer, Luis Munoz, Sascha Kretschmann, Soraya Kharboutli, Regina Gary, Hannah Reimann, Wolf Rösler, Stefan Uderhardt, Holger Bang, Martin Herrmann, Arif Bülent Ekici, Christian Buettner, Katharina Marie Habenicht, Thomas H. Winkler, Gerhard Krönke, Georg Schett
Journal: Nature Medicine (2022)
An update to SPIRIT and CONSORT reporting guidelines to enhance transparency in randomized trials
Authors: Sally Hopewell, Isabelle Boutron, An-Wen Chan, Gary S. Collins, Jennifer A. de Beyer, Asbjørn Hróbjartsson, Camilla Hansen Nejstgaard, Lasse Østengaard, Kenneth F. Schulz, Ruth Tunn, David Moher
Journal: Nature Medicine (2022)
Vessel and tissue recognition during third-space endoscopy using a deep learning algorithm
Authors: Alanna Ebigbo, Robert Mendel, Markus W Scheppach, Andreas Probst, Neal Shahidi, Friederike Prinz, Carola Fleischmann, Christoph Römmele, Stefan Karl Goelder, Georg Braun, David Rauber, Tobias Rueckert, Luis A de Souza, Joao Papa, Michael Byrne, Christoph Palm, Helmut Messmann
Journal: Gut (2022)

In this study, we aimed to develop an artificial intelligence clinical decision support solution to mitigate operator-dependent limitations during complex endoscopic procedures such as endoscopic submucosal dissection and peroral endoscopic myotomy, for example, bleeding and perforation. A DeepLabv3-based model was trained to delineate vessels, tissue structures and instruments on endoscopic still images from such procedures. The mean cross-validated Intersection over Union and Dice Score were 63% and 76%, respectively. Applied to standardised video clips from third-space endoscopic procedures, the algorithm showed a mean vessel detection rate of 85% with a false-positive rate of 0.75/min. These performance statistics suggest a potential clinical benefit for procedure safety, time and also training.
Drivers and determinants of strain dynamics following fecal microbiota transplantation
Authors: Thomas S. B. Schmidt, Simone S. Li, Oleksandr M. Maistrenko, Wasiu Akanni, Luis Pedro Coelho, Sibasish Dolai, Anthony Fullam, Anna M. Glazek, Rajna Hercog, Hilde Herrema, Ferris Jung, Stefanie Kandels, Askarbek Orakov, Roman Thielemann, Moritz von Stetten, Thea Van Rossum, Vladimir Benes, Thomas J. Borody, Willem M. de Vos, Cyriel Y. Ponsioen, Max Nieuwdorp, Peer Bork
Journal: Nature Medicine (2022)

Fecal microbiota transplantation (FMT) is a therapeutic intervention for inflammatory diseases of the gastrointestinal tract, but its clinical mode of action and subsequent microbiome dynamics remain poorly understood. Here we analyzed metagenomes from 316 FMTs, sampled pre and post intervention, for the treatment of ten different disease indications. We quantified strain-level dynamics of 1,089 microbial species, complemented by 47,548 newly constructed metagenome-assembled genomes. Donor strain colonization and recipient strain resilience were mostly independent of clinical outcomes, but accurately predictable using LASSO-regularized regression models that accounted for host, microbiome and procedural variables. Recipient factors and donor-recipient complementarity, encompassing entire microbial communities to individual strains, were the main determinants of strain population dynamics, providing insights into the underlying processes that shape the post-FMT gut microbiome. Applying an ecology-based framework to our findings indicated parameters that may inform the development of more effective, targeted microbiome therapies in the future, and suggested how patient stratification can be used to enhance donor microbiota colonization or the displacement of recipient microbes in clinical practice.
Extracellular Vesicle Secretion by Leukemia Cells <i>In Vivo</i> Promotes CLL Progression by Hampering Antitumor T-cell Responses
Authors: Ernesto Gargiulo, Elodie Viry, Pablo Elías Morande, Anne Largeot, Susanne Gonder, Feng Xian, Nikolaos Ioannou, Mohaned Benzarti, Felix Bruno Kleine Borgmann, Michel Mittelbronn, Gunnar Dittmar, Petr V. Nazarov, Johannes Meiser, Basile Stamatopoulos, Alan G. Ramsay, Etienne Moussay, Jérôme Paggetti
Journal: Blood Cancer Discovery (2022)

Abstract Small extracellular vesicle (sEV, or exosome) communication among cells in the tumor microenvironment has been modeled mainly in cell culture, whereas their relevance in cancer pathogenesis and progression in vivo is less characterized. Here we investigated cancer–microenvironment interactions in vivo using mouse models of chronic lymphocytic leukemia (CLL). sEVs isolated directly from CLL tissue were enriched in specific miRNA and immune-checkpoint ligands. Distinct molecular components of tumor-derived sEVs altered CD8+ T-cell transcriptome, proteome, and metabolome, leading to decreased functions and cell exhaustion ex vivo and in vivo. Using antagomiRs and blocking antibodies, we defined specific cargo-mediated alterations on CD8+ T cells. Abrogating sEV biogenesis by Rab27a/b knockout dramatically delayed CLL pathogenesis. This phenotype was rescued by exogenous leukemic sEV or CD8+ T-cell depletion. Finally, high expression of sEV-related genes correlated with poor outcomes in CLL patients, suggesting sEV profiling as a prognostic tool. In conclusion, sEVs shape the immune microenvironment during CLL progression. Significance: sEVs produced in the leukemia microenvironment impair CD8+ T-cell mediated antitumor immune response and are indispensable for leukemia progression in vivo in murine preclinical models. In addition, high expression of sEV-related genes correlated with poor survival and unfavorable clinical parameters in CLL patients. See related commentary by Zhong and Guo, p. 5. This article is highlighted in the In This Issue feature, p. 1